Cited by 136Vitamin D Research StudiesCutaneous Melanoma Detection and Managementmelanin and skin pigmentation

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Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

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Slominski, Andrzej T, Brożyna, Anna A, Zmijewski, Michal A, Jóźwicki, Wojciech, Jetten, Anton M, Mason, Rebecca S, Tuckey, Robert C, Elmets, Craig A·2017·Laboratory Investigation

DOI 10.1038/labinvest.2017.3PMC PMC5446295

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Abstract

Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2 D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2 D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.

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Authors: Slominski, A. T., Brożyna, A. A., Zmijewski, M. A., Jóźwicki, W., Jetten, A. M., Mason, R. S., Tuckey, R. C., & Elmets, C. A.
Affiliations: University of Alabama at Birmingham (US)
Nicolaus Copernicus University (PL)
Gdańsk Medical University (PL)
National Institutes of Health (US)
The University of Sydney (AU)
The University of Western Australia (AU)
Corresponding author: Slominski, Andrzej T
ORCID: Slominski, Andrzej T
Brożyna, Anna A
Zmijewski, Michal A
Jóźwicki, Wojciech
Jetten, Anton M
Mason, Rebecca S
Tuckey, Robert C
Elmets, Craig A
Venue: Laboratory Investigation
Publisher: Elsevier BV
Published: 2017-06
Volume: 97
Issue: 6
Pages: 706-724
ISSN: 0023-6837 (ISSN-L)
DOI: 10.1038/labinvest.2017.3
PMC: PMC5446295
OpenAlex: W2589902824
Cited by: 136
References: 311
Citations by year: 2026: 3 · 2025: 13 · 2024: 13 · 2023: 14 · 2022: 18 · 2021: 15 · 2020: 24 · 2019: 16 · 2018: 12 · 2017: 8
FWCI: 2.62
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2050 d)
Locations: Laboratory Investigation (publishedVersion)
PubMed (publishedVersion)
UWA Profiles and Research Repository (UWA) (acceptedVersion, other-oa)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Veterans Affairs (I01BX003395)
Narodowym Centrum Nauki
National Institutes of Health (Z01-ES-101586)
National Health and Medical Research Council (1070688)
National Cancer Institute (R01CA193885)
National Institute of Environmental Health Sciences (Z01ES101586)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR066505, R01AR052190, R01AR056666)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Keywords: vitamin D signaling, melanoma, vitamin D receptor, vitamin D binding protein, CYP27B1, CYP24A1, CYP27A1, CYP2R1, CYP11A1, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D, UV-B radiation, melanoma progression, survival outcomes, single nucleotide polymorphisms, photoprotection
MeSH terms: Animals, Cytochrome P-450 Enzyme System, Epidermis, Humans, Melanoma, Ultraviolet Rays, Vitamin D, Signal Transduction, Receptors, Calcitriol, Disease Progression, Mice

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Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

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